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Broadly active zinc finger protein-guided transcriptional activation of HIV-1
Human immunodeficiency virus type 1 (HIV-1) causes a persistent viral infection resulting in the demise of immune regulatory cells. Clearance of HIV-1 infection results in integration of proviral DNA into the genome of host cells, which provides a means for evasion and long-term persistence. A thera...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726486/ https://www.ncbi.nlm.nih.gov/pubmed/33335944 http://dx.doi.org/10.1016/j.omtm.2020.10.018 |
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author | Scott, Tristan A. O’Meally, Denis Grepo, Nicole Anne Soemardy, Citradewi Lazar, Daniel C. Zheng, Yue Weinberg, Marc S. Planelles, Vicente Morris, Kevin V. |
author_facet | Scott, Tristan A. O’Meally, Denis Grepo, Nicole Anne Soemardy, Citradewi Lazar, Daniel C. Zheng, Yue Weinberg, Marc S. Planelles, Vicente Morris, Kevin V. |
author_sort | Scott, Tristan A. |
collection | PubMed |
description | Human immunodeficiency virus type 1 (HIV-1) causes a persistent viral infection resulting in the demise of immune regulatory cells. Clearance of HIV-1 infection results in integration of proviral DNA into the genome of host cells, which provides a means for evasion and long-term persistence. A therapeutic compound that specifically targets and sustainably activates a latent HIV-1 provirus could be transformative and is the goal for the “shock-and-kill” approach to a functional cure for HIV-1. Substantial progress has been made toward the development of recombinant proteins that target specific genomic loci for gene activation, repression, or inactivation by directed mutations. However, most of these modalities are too large or too complex for efficient therapeutic application. We describe here the development and testing of a novel recombinant zinc finger protein transactivator, ZFP-362-VPR, which specifically and potently enhances proviral HIV-1 transcription both in established latency models and activity across different viral clades. Additionally, ZFP-362-VPR-activated HIV-1 reporter gene expression in a well-established primary human CD4(+) T cell latency model and off-target pathways were determined by transcriptome analyses. This study provides clear proof of concept for the application of a novel, therapeutically relevant, protein transactivator to purge cellular reservoirs of HIV-1. |
format | Online Article Text |
id | pubmed-7726486 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-77264862020-12-16 Broadly active zinc finger protein-guided transcriptional activation of HIV-1 Scott, Tristan A. O’Meally, Denis Grepo, Nicole Anne Soemardy, Citradewi Lazar, Daniel C. Zheng, Yue Weinberg, Marc S. Planelles, Vicente Morris, Kevin V. Mol Ther Methods Clin Dev Original Article Human immunodeficiency virus type 1 (HIV-1) causes a persistent viral infection resulting in the demise of immune regulatory cells. Clearance of HIV-1 infection results in integration of proviral DNA into the genome of host cells, which provides a means for evasion and long-term persistence. A therapeutic compound that specifically targets and sustainably activates a latent HIV-1 provirus could be transformative and is the goal for the “shock-and-kill” approach to a functional cure for HIV-1. Substantial progress has been made toward the development of recombinant proteins that target specific genomic loci for gene activation, repression, or inactivation by directed mutations. However, most of these modalities are too large or too complex for efficient therapeutic application. We describe here the development and testing of a novel recombinant zinc finger protein transactivator, ZFP-362-VPR, which specifically and potently enhances proviral HIV-1 transcription both in established latency models and activity across different viral clades. Additionally, ZFP-362-VPR-activated HIV-1 reporter gene expression in a well-established primary human CD4(+) T cell latency model and off-target pathways were determined by transcriptome analyses. This study provides clear proof of concept for the application of a novel, therapeutically relevant, protein transactivator to purge cellular reservoirs of HIV-1. American Society of Gene & Cell Therapy 2020-10-27 /pmc/articles/PMC7726486/ /pubmed/33335944 http://dx.doi.org/10.1016/j.omtm.2020.10.018 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Scott, Tristan A. O’Meally, Denis Grepo, Nicole Anne Soemardy, Citradewi Lazar, Daniel C. Zheng, Yue Weinberg, Marc S. Planelles, Vicente Morris, Kevin V. Broadly active zinc finger protein-guided transcriptional activation of HIV-1 |
title | Broadly active zinc finger protein-guided transcriptional activation of HIV-1 |
title_full | Broadly active zinc finger protein-guided transcriptional activation of HIV-1 |
title_fullStr | Broadly active zinc finger protein-guided transcriptional activation of HIV-1 |
title_full_unstemmed | Broadly active zinc finger protein-guided transcriptional activation of HIV-1 |
title_short | Broadly active zinc finger protein-guided transcriptional activation of HIV-1 |
title_sort | broadly active zinc finger protein-guided transcriptional activation of hiv-1 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726486/ https://www.ncbi.nlm.nih.gov/pubmed/33335944 http://dx.doi.org/10.1016/j.omtm.2020.10.018 |
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